Structural chromosome abnormalities, increased DNA strand breaks and DNA strand break repair deficiency in dermal fibroblasts from old female human donors

Faiza Kalfalah, Sabine Seggewiß, Regina Walter, Julia Tigges, María Moreno-Villanueva, Alexander Bürkle, Sebastian Ohse, Hauke Busch, Melanie Boerries, Barbara Hildebrandt, Brigitte Royer-Pokora, Fritz Boege

Abstract

Dermal fibroblasts provide a paradigmatic model of cellular adaptation to long-term exogenous stress and ageing processes driven thereby. Here we addressed whether fibroblast ageing analysedex vivo entails genome instability. Dermal fibroblasts from human female donors aged 20-67 years were studied in primary culture at low population doubling. Under these conditions, the incidence of replicative senescence and rates of age-correlated telomere shortening were insignificant. Genome-wide gene expression analysis revealed age-related impairment of mitosis, telomere and chromosome maintenance and induction of genes associated with DNA repair and non-homologous end-joining, most notably XRCC4 and ligase 4. We observed an age-correlated drop in proliferative capacity and age-correlated increases in heterochromatin marks, structural chromosome abnormalities (deletions, translocations and chromatid breaks), DNA strand breaks and histone H2AX-phosphorylation. In a third of the cells from old and middle-aged donors repair of X-ray induced DNA strand breaks was impaired despite up-regulation of DNA repair genes. The distinct phenotype of genome instability, increased heterochromatinisation and (in 30% of the cases futile) up-regulation of DNA repair genes was stably maintained over several cell passages indicating that it represents a feature of geroconversion that is distinct from cellular senescence, as it does not encompass a block of proliferation.

OriginalspracheEnglisch
ZeitschriftAging
Jahrgang7
Ausgabenummer2
Seiten (von - bis)110-22
Seitenumfang13
ISSN1945-4589
DOIs
PublikationsstatusVeröffentlicht - 02.2015

Fingerprint

Untersuchen Sie die Forschungsthemen von „Structural chromosome abnormalities, increased DNA strand breaks and DNA strand break repair deficiency in dermal fibroblasts from old female human donors“. Zusammen bilden sie einen einzigartigen Fingerprint.

Zitieren